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Articles by L. A Cupples
Total Records ( 8 ) for L. A Cupples
  D Corella , G Peloso , D. K Arnett , S Demissie , L. A Cupples , K Tucker , C. Q Lai , L. D Parnell , O Coltell , Y. C Lee and J. M. Ordovas

Background  Nutrigenetics studies the role of genetic variation on interactions between diet and health, aiming to provide more personalized dietary advice. However, replication has been low. Our aim was to study interaction among a functional APOA2 polymorphism, food intake, and body mass index (BMI) in independent populations to replicate findings and to increase their evidence level.

Methods  Cross-sectional, follow-up (20 years), and case-control analyses were undertaken in 3 independent populations. We analyzed gene-diet interactions between the APOA2 –265T>C polymorphism and saturated fat intake on BMI and obesity in 3462 individuals from 3 populations in the United States: the Framingham Offspring Study (1454 whites), the Genetics of Lipid Lowering Drugs and Diet Network Study (1078 whites), and Boston–Puerto Rican Centers on Population Health and Health Disparities Study (930 Hispanics of Caribbean origin).

Results  Prevalence of the CC genotype in study participants ranged from 10.5% to 16.2%. We identified statistically significant interactions between the APOA2 –265T>C and saturated fat regarding BMI in all 3 populations. Thus, the magnitude of the difference in BMI between the individuals with the CC and TT+TC genotypes differed by saturated fat. A mean increase in BMI of 6.2% (range, 4.3%-7.9%; P = .01) was observed between genotypes with high– (≥22 g/d) but not with low– saturated fat intake in all studies. Likewise, the CC genotype was significantly associated with higher obesity prevalence in all populations only in the high–saturated fat stratum. Meta-analysis estimations of obesity for individuals with the CC genotype compared with the TT+TC genotype were an odds ratio of 1.84 (95% confidence interval, 1.38-2.47; P < .001) in the high–saturated fat stratum, but no association was detected in the low–saturated fat stratum (odds ratio, 0.81; 95% confidence interval, 0.59-1.11; P = .18).

Conclusion  For the first time to our knowledge, a gene-diet interaction influencing BMI and obesity has been strongly and consistently replicated in 3 independent populations.

  R. S Vasan , S Demissie , M Kimura , L. A Cupples , C White , J. P Gardner , X Cao , D Levy , E. J Benjamin and A. Aviv

Background— Leukocyte telomere length (LTL) decreases over the adult life course owing to the cumulative burden of oxidative stress, inflammation, and exposure to vascular risk factors. Left ventricular (LV) mass is a biomarker of long-standing exposure to cardiovascular disease risk factors. We hypothesized that LTL is related inversely to LV mass.

Methods and Results— We related LTL (measured by Southern blot analysis) to echocardiographic LV mass and its components (LV diastolic dimension and LV wall thickness) in 850 Framingham Heart Study participants (mean age 58 years, 58% women) using multivariable linear regression with adjustment for age, sex, height, weight, systolic blood pressure, hypertension treatment, and smoking. Overall, multivariable-adjusted LTL was positively related to LV mass (β-coefficient per SD increase 0.072; P=0.001), LV wall thickness (β=0.053; P=0.01), and LV diastolic dimension (β=0.035; P=0.09). We observed effect modification by hypertension status (P for interaction=0.02 for LV mass); LTL was more strongly associated with LV mass and LV wall thickness in individuals with hypertension (β-coefficient per SD increment of 0.10 and 0.08, respectively; P<0.01 for both). Participants with hypertension who were in the top quartile of LV mass had LTL that was 250 base pairs longer than those in the lowest quartile (P for trend across quartiles=0.009).

Conclusions— In contrast to our expectation, in the present community-based sample, LTL was positively associated with LV mass and wall thickness, especially so in participants with hypertension. These data are consistent with the hypothesis that longer LTL may be a marker of propensity to LV hypertrophy.

  A. C Morrison , J. F Felix , L. A Cupples , N. L Glazer , L. R Loehr , A Dehghan , S Demissie , J. C Bis , W. D Rosamond , Y. S Aulchenko , Y. A Wang , T Haritunians , A. R Folsom , F Rivadeneira , E. J Benjamin , T Lumley , D Couper , B. H Stricker , C. J O'Donnell , K. M Rice , P. P Chang , A Hofman , D Levy , J. I Rotter , E. R Fox , A. G Uitterlinden , T. J Wang , B. M Psaty , J. T Willerson , C. M van Duijn , E Boerwinkle , J. C. M Witteman , R. S Vasan and N. L. Smith

Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2 366 858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

Methods and Results—

Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10–7. Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10–7). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10–5) but did not meet genome-wide significance.


This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

  N. L Smith , J. F Felix , A. C Morrison , S Demissie , N. L Glazer , L. R Loehr , L. A Cupples , A Dehghan , T Lumley , W. D Rosamond , W Lieb , F Rivadeneira , J. C Bis , A. R Folsom , E Benjamin , Y. S Aulchenko , T Haritunians , D Couper , J Murabito , Y. A Wang , B. H Stricker , J. S Gottdiener , P. P Chang , T. J Wang , K. M Rice , A Hofman , S. R Heckbert , E. R Fox , C. J O'Donnell , A. G Uitterlinden , J. I Rotter , J. T Willerson , D Levy , C. M van Duijn , B. M Psaty , J. C. M Witteman , E Boerwinkle and R. S. Vasan

Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2 478 304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

Methods and Results—

Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10–7. During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10–8), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10–8), which was 6.3 kb from LRIG3.


We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

  K Musunuru , G Lettre , T Young , D. N Farlow , J. P Pirruccello , K. G Ejebe , B. J Keating , Q Yang , M. H Chen , N Lapchyk , A Crenshaw , L Ziaugra , A Rachupka , E. J Benjamin , L. A Cupples , M Fornage , E. R Fox , S. R Heckbert , J. N Hirschhorn , C Newton Cheh , M. M Nizzari , D. N Paltoo , G. J Papanicolaou , S. R Patel , B. M Psaty , D. J Rader , S Redline , S. S Rich , J. I Rotter , H. A Taylor , R. P Tracy , R. S Vasan , J. G Wilson , S Kathiresan , R. R Fabsitz , E Boerwinkle , S. B Gabriel and for the NHLBI Candidate Gene Association Resource

The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40 000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

Methods and Results—

CARe has assembled DNA samples for >40 000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.


The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of 2000 biological candidate loci in all participants and genome-wide association study in 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

  M Preuss , I. R Konig , J. R Thompson , J Erdmann , D Absher , T. L Assimes , S Blankenberg , E Boerwinkle , L Chen , L. A Cupples , A. S Hall , E Halperin , C Hengstenberg , H Holm , R Laaksonen , M Li , W Marz , R McPherson , K Musunuru , C. P Nelson , M Susan Burnett , S. E Epstein , C. J O'Donnell , T Quertermous , D. J Rader , R Roberts , A Schillert , K Stefansson , A. F. R Stewart , G Thorleifsson , B. F Voight , G. A Wells , A Ziegler , S Kathiresan , M. P Reilly , N. J Samani , H Schunkert and on behalf of the CARDIoGRAM Consortium

Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed.

Methods and Results—

CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes >22 000 cases with CAD, MI, or both and >60 000 controls; and unifies samples from the Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium. Genotyping was carried out on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies. On average, 2.2 million single nucleotide polymorphisms were generated per study. The results from each study are combined using meta-analysis. As proof of principle, we meta-analyzed risk variants at 9p21 and found that rs1333049 confers a 29% increase in risk for MI per copy (P=2x10–20).


CARDIoGRAM is poised to contribute to our understanding of the role of common genetic variation on risk for CAD and MI.

  A. D Johnson , M Kavousi , A. V Smith , M. H Chen , A Dehghan , T Aspelund , J. P Lin , C. M van Duijn , T. B Harris , L. A Cupples , A. G Uitterlinden , L Launer , A Hofman , F Rivadeneira , B Stricker , Q Yang , C. J O'Donnell , V Gudnason and J. C. Witteman

Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 x 10–324) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 x 10–13), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain ~18.0 and ~1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 x 10–13), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.

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